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EP3972613A1 - Utilisation d'ions métalliques pour potentialiser les effets thérapeutiques de l'arsenic - Google Patents

Utilisation d'ions métalliques pour potentialiser les effets thérapeutiques de l'arsenic

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Publication number
EP3972613A1
EP3972613A1 EP20726163.7A EP20726163A EP3972613A1 EP 3972613 A1 EP3972613 A1 EP 3972613A1 EP 20726163 A EP20726163 A EP 20726163A EP 3972613 A1 EP3972613 A1 EP 3972613A1
Authority
EP
European Patent Office
Prior art keywords
disease
arsenic
cells
composition
as2o3
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP20726163.7A
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German (de)
English (en)
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EP3972613B1 (fr
Inventor
François Rieger
Frédéric BATTEUX
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Medsenic
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Medsenic
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Publication of EP3972613A1 publication Critical patent/EP3972613A1/fr
Application granted granted Critical
Publication of EP3972613B1 publication Critical patent/EP3972613B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/36—Arsenic; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/242—Gold; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention pertains to the field of medicine and is based on the unexpected finding that therapeutic effects of arsenic can be potentiated by administration of divalent metal ions, and most specifically by Cu 2+ ions.
  • Arsenic compounds have widely been used as traditional medicines in many parts of the world for the treatment of various diseases such as psoriasis, syphilis, or rheumatic arthritis for over two thousand years. Many different arsenic preparations have been developed and used during the long history of these agents. For example, the Fowler's solution, which contains 1 % potassium arsenite (KASO2), was prescribed for years as a remedy for leukemias and even as a tonic.
  • KASO2 potassium arsenite
  • arsenical compounds are notably toxic and carcinogenic, with side effects such as cirrhosis of the liver, idiopathic portal hypertension, urinary bladder cancer, and skin cancers. Recently however, several arsenic compounds have been rediscovered and formulated to treat different diseases, such as cancer.
  • Arsenic Trioxide (AS2O3, also noted“ATO” in the present text) occurs to be one of the most effective novel anticancer ("antineoplastic” or “cytotoxic”) agents.
  • ATO has been approved by the US FDA for the treatment of acute promyelocytic leukemia (APL) resistant to "first line” agents, namely all- trans retinoic acid (ATRA). It has been shown that arsenic trioxide induces cancer cells to undergo apoptosis.
  • Arsenic Trioxide is also known or currently investigated as an agent against other diseases, such as auto-immune diseases.
  • Zhang et al. (PNAS 2015; Vol. 112, No. 49) used a human proteome microarray to identify arsenic- binding proteins. They identified 360 arsenic-binding proteins and found proteins of glycolysis to be highly enriched. They suggest that glycolysis in general and the rate-limiting enzyme hexokinase-2 of the glycolytic pathway in particular, play a key role in mediating the anticancer activity of arsenic.
  • AS2O3 is a pharmacologically active compound, with highly toxic properties at high concentrations or long term exposures.
  • EMA authorizations and SLE (Phase 2a; terminated) or GvHDc (Phase 2, ongoing) only present reversible Adverse Effects (AE) for the intravenous (IV) dosage generally adopted (0.15 mg/kg/day over a one - two (and sometimes up to five) month periods of IV treatment).
  • the AEs are potential important threats to the health status of the patients, the most unwelcomed ones being a transient increase in the cardiac QT widening, possibly together with changes in blood electrolytes levels and hepatic increased release of liver enzymes. These AEs are carefully monitored, essentially reversible - but necessitate transient suspensions of the treatment for a few days - and occur in an important proportion of the patients. Typically, even when patients are recruited under strict inclusion/exclusion rules, about one third of them develop AEs.
  • the inventors investigated the possibilities to increase the effect of a given dose of the API by using in parallel, drugs or molecules able to increase the cell stress.
  • ROS Radical Oxygen Species
  • the amount of hydrogen peroxide is regulated by heme peroxidases that accelerate its dismutation and by the glutathione peroxidase (GPx) that catalyzes its reduction by glutathione (GSH).
  • GPx glutathione peroxidase
  • Other ROS exist, such as peroxyl radicals RO2 ' , hydroperoxides RO2H and alkoxyl radicals RO ' .
  • the H 2 0 2 -degrading Fenton reaction (reaction (iii) above) is typically catalyzed by free iron bivalent ions and leads to the generation of ⁇ H.
  • the Fenton reaction is admittedly localized at the endoplasmic reticulum or in perinuclear locations, but not in mitochondria or other cell compartments (Liu Q, et at. Proc Natl Acad Sci USA 2004;101 :4302-7).
  • Sources of H2O2 could be mitochondria (superoxide dismutase reaction), peroxisomes (acyl-CoA oxidase reaction) and amyloid beta of senile plaques (superoxide dismutase-like reactions).
  • H2O2 that escapes the cell antioxidant machinery might be converted nonenzymatically in a perinuclear- localized Fenton reaction and act as an RNA- or DNA-damaging agent.
  • the inventors investigated the possibility to increase the effect of a given dose of an arsenic compound by using in parallel, drugs or molecules able to increase the cell stress through the activation of the Fenton reaction. To this aim, they tested several elements known to increase this reaction, starting with the well-known Iron salts, as well as others, such as Zn, Mn, Mg, Cu, Au, etc. ...
  • Cu 2+ ions specifically display strong synergic features of action with arsenic, including all searched features, i.e., H2O2 cell production, apoptosis induction increase and physiologic effects in a basic and highly significant test for the immune system function, the Mixed Lymphocyte Reaction (MLR), developed with mouse cells of different genetic backgrounds.
  • MLR Mixed Lymphocyte Reaction
  • the present invention thus pertains to a medicament comprising an arsenic compound and a metal ion selected from the group consisting of Cu 2+ , without omitting more classical Fenton-agents such as Au 2+ , Fe 2+ , Zn 2+ , Mn 2+ , Mg 2+ and mixtures thereof.
  • the invention also relates to the use of a combination of a Cu 2+ salt and an arsenic compound, in the treatment of various diseases including neoplastic diseases, autoimmune diseases, inflammatory diseases and neuro-degenerative diseases, wherein the arsenic compound and the Cu 2+ salt are administered to a patient simultaneously or sequentially.
  • the Cu 2+ ions increase the therapeutic effects of arsenic.
  • Figure 1 Effects of AS2O3 at increasing concentrations on the production of H2O2, GSH and cell viability in HL60 cells.
  • Figure 2 Effects of FeSC at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in HL60 cells.
  • Figure 3 Effects of HAuCh at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in HL60 cells.
  • Figure 4 Effects of ZnSC at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in H L60 cells.
  • Figure 5 Effects of ZnC at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in HL60 cells.
  • Figure 6 Effects of MnSC at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in H L60 cells.
  • Figure 7 Effects of MnCh at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in HL60 cells.
  • Figure 8 Effects of CuSC at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in HL60 cells.
  • Figure 9 Effects of CuCh at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the production of H2O2 and cell viability in HL60 cells.
  • Figure 10 Effects of AS2O3 (1 mM) combined to CuC (1 or 4 mM) on the production of H2O2 and cell viability in HL60 cells.
  • Figure 11 Effects of AS2O3 (1 mM) combined to increasing concentrations of CuC (0.5 to 4 pM) on the production of GSH and cell viability in HL60 cells.
  • Figure 12 Effects of AS2O3 on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • MLR mixed lymphocyte reaction
  • Figure 13 Effects of FeS0 4 at increasing concentrations, alone or combined to AS2O3 at 1 pM, on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • Figure 14 Effects of HAuCb at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • Figure 15 Effects of ZnSCb and ZnCb at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • MLR mixed lymphocyte reaction
  • Figure 16 Effects of MnSCb and MnCb at increasing concentrations, alone or combined to AS2O3 at 1 mM, on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • MLR mixed lymphocyte reaction
  • Figure 17 Effects of CuSCb and CuCb at increasing concentrations, alone or combined to AS2O3 at 1 pM, on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • MLR mixed lymphocyte reaction
  • Figure 18 Effects of CuCb at increasing concentrations, alone or combined to AS2O3 at 1 pM, on the production of H2O2 and cell viability in A20 cells.
  • Figure 19 Effects of AS2O3 (1 pM) combined to increasing concentrations of CuC (0.5 to 4 pM) on the production of GSH and cell viability in A20 cells.
  • Figure 20 Effects of Ash at increasing concentrations on the production of H2O2, GSH and cell viability in HL60 cells.
  • Figure 21 Effects of CuCb at increasing concentrations, alone or combined to Asbat 1 pM, on the production of H2O2 and cell viability in HL60 cells.
  • FIG 22 Effects of AS2O3 and Asb on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • MLR mixed lymphocyte reaction
  • Figure 23 Effects of CuCb at increasing concentrations, alone or combined to Asb at 1 pM, on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction (MLR).
  • MLR mixed lymphocyte reaction
  • Figure 24 Effect of treatments on the onset of skin abnormalities (alopecia) in chronic GvHD. Pictures represent the development of alopecia in the different experimental groups.
  • D Allogeneic + AS2O3 2.5 pg/g + CuCb 2.5 pg/g (3 mice - none with alopecia).
  • E Allogeneic + CuCb 2.5 pg/g (2 mice - 1 with alopecia).
  • F Allogeneic + AS2O3 2.5 pg/g + CuCb 10 pg/g (2 mice - none with alopecia).
  • G Allogeneic + CuCb 10 pg/g (5 mice - none with alopecia).
  • H Allogeneic + AS2O3 5 pg/g (5 mice - 1 with alopecia).
  • Figure 25 Effects of the treatments on mice weight during the evolution of GVHD.
  • A syngeneic and allogeneic groups treated or not with AS2O3 (2.5 pg/g or 5 pg/g, as indicated).
  • B syngeneic group and allogenic groups treated or not with (AS2O3 2.5 pg/g and CuCh 2.5 pg/g).
  • C syngeneic group and allogenic groups treated or not with (AS2O3 2,5 pg/g and CuCh 10 pg/g).
  • Figure 26 Effects of the treatments on vasculitis (clinical scoring: ear thicknesses) during the evolution of GVHD.
  • C Thickness of the mice ears in the syngeneic and allogenic groups treated or not with AS2O3 at 2.5 pg/g and CuC at 10 pg/g.
  • FIG. 27 Effects of the treatments on the liver: transaminases levels in each mouse blood.
  • Figure 28 Effects of the treatments on mice weights during the evolution of GVFID. Mice treated with copper at 0 / 0.2 pg/g and 0.5 pg/g.
  • the terms“treat”,“treatment” and“treating” refer to any reduction of one or more symptom(s) associated with a disease, such as, for example, a reduction of the occurrence and/or severity of symptoms in an autoimmune disease, and/or an increase in survival that results from the administration of a composition according to the invention to cancer patients. These terms are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • “Treatment” as used herein covers any treatment of a disease in a mammal, and includes: preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e., causing regression of the disease.
  • the therapeutic agent may be administered before, during or after the onset of disease or injury.
  • the treatment of ongoing disease where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest.
  • the phrase“ameliorating at least one symptom of” refers to decreasing one or more symptoms of the disease or condition for which the subject is being treated.
  • the disease or condition being treated is a hematological malignancy, wherein the one or more symptoms ameliorated include, but are not limited to, weakness, fatigue, shortness of breath, easy bruising and bleeding, frequent infections, enlarged lymph nodes, distended or painful abdomen (due to enlarged abdominal organs), bone or joint pain, fractures, unplanned weight loss, poor appetite, night sweats, persistent mild fever, and decreased urination (due to impaired kidney function).
  • preventing etc., indicate an approach for preventing, inhibiting, or reducing the likelihood of the occurrence or recurrence of, a disease or condition. It also refers to delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition. As used herein,“prevention” and similar words also include reducing the intensity, effect, symptoms and/or burden of a disease or condition prior to onset or recurrence of the disease or condition.
  • an effective amount refers to the amount of an arsenic-containing compound and of a metal ion sufficient to prevent, ameliorate one symptom of, or treat a disease, e.g., a hematological malignancy or an autoimmune disease contemplated herein.
  • A“prophylactically effective amount” refers to an amount of an arsenic- containing compound + a metal ion effective to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount is less than the therapeutically effective amount.
  • A“therapeutically effective amount” of an arsenic-containing compound + a metal ion may vary according to factors such as the disease state, age, sex, and weight of the individual, and the natures of the agent (arsenic compound) and co-agent (metal ion) to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the agent are outweighed by the therapeutically beneficial effects.
  • the term“therapeutically effective amount” includes an amount that is effective to “treat” a subject (e.g., a patient).
  • compositions and methods include the recited elements, but not excluding others.
  • Consist essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consist of shall mean excluding more than trace amounts of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
  • the present invention pertains to a medicament comprising an arsenic compound and a metal ion selected amongst Cu 2+ , Au 2+ , Fe 2+ , Zn 2+ , Mn 2+ , Mg 2+ and mixtures thereof.
  • Medicaments according to the present invention preferably comprise arsenic trioxide or arsenic triiodide, together with a metal ion as listed above, such as Cu 2+ , alone or combined to any other metal ion selected amongst Au 2+ , Fe 2+ , Zn 2+ Mn 2+ and Mg 2+ .
  • the Cu 2+ ions are in the form of a salt such as copper sulfate (CuSCh) or copper(ll) chloride (CuCh).
  • the actual dosing for ATO when used in the treatment of hematologic cancers is 0.15 mg/kg/day.
  • the results disclosed in the experimental part below demonstrate that when ATO is used in combination with Cu 2+ , its effects are potentiated. Flence, the same therapeutic efficacy should be obtained with a lower dose of ATO in the presence of Cu 2+ as that of the currently used ATO formulation.
  • the physician can also choose to combine with Cu 2+ ions the same concentration of ATO as that currently approved in combination, to increase the therapeutic effects of ATO.
  • the composition according to the present invention is formulated so that one daily dose comprises between 0.01 to 0.15 mg/kg/day of arsenic trioxide (corresponding to 0.1 to 1.6 pmol/kg of arsenic atoms).
  • the composition according to the present invention is formulated so that one daily dose comprises between 0.01 to 0.05 mg/kg/day of arsenic trioxide.
  • the composition according to the present invention is formulated so that one daily dose comprises between 0.05 to 0.10 mg/kg/day of arsenic trioxide.
  • composition according to the present invention is formulated so that one daily dose comprises between 0.10 to 0.15 mg/kg/day of arsenic trioxide.
  • arsenic compound different from arsenic trioxide when used in the frame of the present invention, its dosage can be chosen so that the amount of arsenic atoms administered to the patient is the same as that in the dosages indicated above for arsenic trioxide.
  • the composition according to the present invention is formulated so that one daily dose comprises between 0.05 pmol/kg and 10 pmol/kg of Cu 2+ , preferably between 0.06 pmol/kg and 2 pmol/kg of Cu 2+ , for example between 0.3 pmol/kg and 1.1 pmol/kg of Cu 2+ .
  • the composition according to the present invention is formulated so that one daily dose comprises about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.15, 0.2, 0.25, 0.30, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 pmol/kg of Cu 2+ .
  • Any disease which has already been successfully treated by ATO or any other arsenic compound can beneficiate from a treatment with a composition as above-described, since the combination of arsenic and the metal ions such as Cu 2+ increase the beneficial effects of arsenic.
  • the present invention thus pertains to the use of a composition as above- described in treating a disease selected amongst:
  • the present invention also pertains to the use of a combination of a Cu 2+ salt (e.g., CU2SO4 or CuCh) and an arsenic compound (as above-described), in the treatment of a disease selected from the group consisting of a neoplastic disease, an autoimmune disease and an inflammatory disease, wherein said arsenic compound and said Cu 2+ salt are administered to a patient simultaneously or sequentially.
  • a Cu 2+ salt e.g., CU2SO4 or CuCh
  • an arsenic compound as above-described
  • the present invention thus also pertains to the use of a composition comprising an arsenic compound, for treating a disease selected from the group consisting of a neoplastic disease, an autoimmune disease and an inflammatory disease, wherein said arsenic compound is administered to a patient in combination with a Cu 2+ salt or any other metallic ions with similar properties.
  • the composition comprising an arsenic compound is administered before the composition comprising a Cu 2+ salt.
  • the composition comprising an arsenic compound is administered after the composition comprising a Cu 2+ salt. In both cases, the arsenic compound and the Cu 2+ salt are administered in a time interval preferably not exceeding 12 hours.
  • the composition comprising an arsenic compound and the composition comprising a Cu 2+ salt are administered simultaneously. Whatever the administration sequence, the arsenic compound and the Cu 2+ salt are administered either via the same route or via different routes.
  • the present invention pertains to the use of a salt of a metal ion, e.g. a Cu 2+ salt, for potentiating/increasing the therapeutic effects of an arsenic compound as described above.
  • a salt of a metal ion e.g. a Cu 2+ salt
  • Cu 2+ ions or the like can for example be used for potentiating the therapeutic effects of ATO or any other arsenic compound used in the treatment of a disease such as a neoplastic disease, an autoimmune disease, or more generally an inflammatory disease.
  • potentiating is herein meant that using a same amount of an arsenic compound (e.g., ATO), the therapeutic effects of arsenic are significantly increased when the patient also receives Cu 2+ ions, although the administration of Cu 2+ ions alone is without any measurable effect.
  • ATO arsenic compound
  • This potentiation or synergy has been demonstrated at least in vitro, as illustrated in examples 1 to 9 below (which show a significant increase of H2O2 cell production and apoptosis induction, as well as physiologic effects in a Mixed Lymphocyte Reaction (MLR), which is a highly significant assay for the immune system function).
  • MLR Mixed Lymphocyte Reaction
  • the present invention also pertains to a method for treating a disease selected from the group consisting of a neoplastic disease, an autoimmune disease, or more generally an inflammatory disease in a patient in need thereof, comprising the step of administering an effective dose of an arsenic compound (as above defined) and of a metal ion selected amongst Cu 2+ , Au 2+ , Fe 2+ , Zn 2+ , Mn 2+ , Mg 2+ and mixtures thereof to said patient.
  • a Cu 2+ salt is administered to the patient.
  • the clinician will adapt the dosing and scheme of administration of arsenic compound and Cu 2+ salt or the like.
  • the arsenic compound is arsenic trioxide.
  • a therapeutically effective amount is at most 0.30 mg/kg/day of ATO, for example 0.30, 0.25, 0.20 or 0.15 mg/kg/day of ATO and a prophylactically effective amount is at most 0.15 mg/kg/day of ATO, for example 0.15, 0.10 or 0.05 mg/kg/day of ATO or even less, down to 0.01 mg/kg/day.
  • the patient is administered a daily dose that comprises between 0.01 to 0.15 mg/kg/day of arsenic trioxide, during 1 to 80 days.
  • the patient is administered a daily dose that comprises between 0.01 to 0.05 mg/kg/day of arsenic trioxide, during 1 to 80 days, with the possibility to reiterate the treatment if needed for reaching a satisfactory level of clinical efficacy.
  • the patient is administered a daily dose that comprises between 0.05 to 0.10 mg/kg/day of arsenic trioxide, during 1 to 80 days.
  • the patient is administered a daily dose that comprises between 0.10 to 0.15 mg/kg/day of arsenic trioxide, during 1 to 80 days.
  • the patient is administered a daily dose that comprises between 0.05 pmol/kg and 10 pmol/kg of Cu 2+ , preferably between 0.06 pmol/kg and 2 pmol/kg of Cu 2+ , for example between 0.3 pmol/kg and 1.1 pmol/kg of Cu 2+ , as long as he/she receives the arsenic compound.
  • the patient receives about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.15, 0.2, 0.25, 0.30, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 pmol/kg of Cu 2+ , each day, as long as he/she receives the arsenic compound.
  • the Cu 2+ ions can be, for example, in the form of copper sulfate or copper(ll) chloride.
  • the arsenic compound and the Cu 2+ salt are administered to the patient simultaneously or sequentially, through the same or a different route of administration.
  • the Cu 2+ salt can be administered to the patient every day, every other day, two or three times a week, or even weekly.
  • the arsenic compound is administered intravenously.
  • the arsenic compound is administered orally.
  • the arsenic compound is administered topically.
  • the arsenic compound is administered as an aerosol.
  • the arsenic compound and the Cu 2+ salt are in the same pharmaceutical composition.
  • This invention thus relates to a method of administering to a subject, a pharmaceutical composition comprising an arsenic compound and a Cu 2+ salt, comprising the steps of providing said pharmaceutical composition, and administering said pharmaceutical composition to said subject.
  • This invention further relates to a method of treating an autoimmune disease, and more generally an inflammatory disease, or a neoplastic disease such as a cancer or a tumor in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of the pharmaceutical composition comprising an arsenic compound and a Cu 2+ salt.
  • Neoplasms include benign tumors and malignant tumors (e.g., leukemias or colon tumors or prostate cancer) that are either invasive or noninvasive. Malignant neoplasms are distinguished from benign neoplasms in that the former show a greater degree of anaplasia, or loss of differentiation and orientation of cells, and have the properties of invasion and metastasis
  • Cancers that can be treated according to the present invention include solid and non solid cancers.
  • the cancer is a hematological malignancy.
  • Example of hematological malignancies that can be treated according to the invention include acute myeloid leukemia; acute nonlymphocytic leukemia; myeloblastic leukemia, promyelocytic leukemia; chronic myelomonocytic leukemia; monocytic leukemia; erythroleukemia; acute neutrophilic leukemia; myelodysplastic syndrome; acute promyelocytic leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; hairy cell leukemia; myeloproliferative neoplasms; Hodgkin's lymphoma; non-Hodgkin's lymphoma; myeloma; giant cell myeloma; indolent myeloma; localized myeloma; multiple myelo
  • said hematological malignancy is acute promyelocytic leukemia (APL).
  • APL is newly diagnosed APL.
  • said APL is relapsed or refractory APL.
  • carcinomas e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas
  • carcinomas e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas
  • benign and malignant melanomas myeloproliferative diseases
  • sarcomas particularly Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, and synovial sarcoma
  • tumors of the central nervous system e.g., gliomas, astrocytomas, oligodendrogliomas, e
  • Autoimmune diseases are diseases of the immune system characterized by the production of antibodies (called autoantibodies) which react with antigens (called autoantigens) originating from the tissues of the patient or diseases which are characterized by an activation of immune cells (for example cytotoxic cells) with or without the production of antibodies.
  • autoantibodies antibodies which react with antigens (called autoantigens) originating from the tissues of the patient or diseases which are characterized by an activation of immune cells (for example cytotoxic cells) with or without the production of antibodies.
  • Inflammatory diseases include a vast array of disorders and conditions that are characterized by inflammatory processes, either secondary or primary or even unique (prevalent over other immune mechanisms).
  • Autoimmune diseases and inflammatory diseases that can be treated with a combination of an arsenic compound and a metal ion such as Cu 2+ include, without limitation, systemic lupus erythematosus (SLE); acute disseminated lupus erythematosus; Bechet's disease; juvenile arthritis; Fiessinger-Leroy-Reiter syndrome; gout; osteoarthrosis; polymyositis; myocarditis; autoimmune rheumatoid arthritis (RA); systemic vasculitis; insulin- dependent diabetes mellitus (IDDM; type I diabetes, inflammatory bowel disease (IBD); celiac disease, autoimmune thyroid disease; Sjogren's syndrome, autoimmune gastritis, ulcerative colitis; Crohn's disease; autoimmune hepatitis, primary biliary cirrhosis; primary sclerosing cholangitis; cutaneous autoimmune diseases; autoimmune dilated cardiomyopathy, multiple
  • arsenic compounds especially arsenic trioxide
  • US 2018/325944 The beneficial effects of arsenic compounds, especially arsenic trioxide, has already been reported for multiple sclerosis (US 2018/325944).
  • multiple sclerosis and related syndromes can be treated according to the invention with a combination of an arsenic compound and a metal ion such as Cu 2+ .
  • Particular diseases that can be treated according to the present invention are human diseases or their animal counterparts which are already successfully treated with ATO, such as acute promyelocytic leukemia, systemic lupus erythematosus (SLE), chronic graft versus host disease (GvHD), multiple sclerosis (MS), Sjogren syndrome, rheumatoid arthritis, Crohn’s disease, myelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, malignant glioma, myelodysplastic syndrome, multiple myeloma and liver cancer.
  • the present invention provides a means to potentiate the effects of arsenic when used in the treatment of these diseases, thus enabling to use lower daily doses of ATO or to obtain better therapeutic results with the same dosage as currently used.
  • the HL-60 cell line is a Human Caucasian promyelocytic leukaemia cell line (ATCC n°CCL-240). This line was maintained throughout the experiment, retaining 2x10 5 cells per ml by Flask (Falcon 250mL 75 cm 2 , Reference: 353135) in a RPMI 1640 + GlutaMax culture medium Sigma-Aldrich (Saint-Quentin Fallavier, France) containing 10% Foetal Bovine Serum (Gibco, USA), 1 % penicillin-streptomycin (Gibco, USA), 1 % ciprofloxacine and 1 % fungizone (Gibco, USA).
  • A20 Cell culture is a mouse cell line (ATCC n°TIB-208). This line was maintained throughout the experiment, retaining 2x10 5 cells per ml by Flask (Falcon 250ml_ 75 cm 2 , Reference: 353135) in a RPMI 1640 + GlutaMax culture medium Sigma-Aldrich (Saint-Quentin Fallavier, France) containing 10% Foetal Bovine Serum (Gibco, USA), 1 % penicillin-streptomycin (Gibco, USA), 1 % ciprofloxacine, 1 % fungizone (Gibco, USA) and 1 % 2-mercaptoethanol (Gibco, USA).
  • mice eight week-old female BALB/c and female C57BI6 mice were purchased from Janvier Labs (Le Genest-Saint-lsle, France) and maintained with food and water ad libitum. They were given humane care, according to national guidelines. The spleen cells of each type mouse were used on the culture mixed of lymphocytes (model MLR).
  • the first five divalent cations tested were purchased from Sigma-Aldrich (Saint- Quentin Fallavier, France): CuS04, FeS04, MnS04, ZnS04 as well as HAuCh (Laboratory grades).
  • the FI2O2 production was assessed by spectrofluorimetry using a fusion spectrofluorimeter (Packard). Fluorescence intensity was recorded immediately (TO hour) and after 6 hours of incubation (T6 hours). Fluorescence excitation/emission maxima were for 2’, 7’-dichlorodihydrofluorescein diacetate 485/530 nm.
  • the GSFI production was assessed by spectrofluorimetry using a fusion spectrofluorimeter (Packard). Fluorescence intensity was recorded immediately (TO hour) and after 6 hours of incubation (T6 hours). Fluorescence excitation/emission maxima were for monochlorobimane, 380/461 nm.
  • the medium was removed and cells were stained with 0.5% crystal violet and 30% ethanol in PBS for 30 minutes at room temperature. After two washes in
  • the FI2O2 or GSFI production by the cells were calculated in each condition of treatment as follows:
  • FeS0 4 0.5; 1 ; 2 and 4 pM
  • HAUCI 2 0.125; 0.25; 0.5; 1 pM
  • e- AS2O3 with or without divalent cations on the proliferation of C57BI6 CD4 T cells in vitro Cell proliferation in mixed lymphocyte cultures.
  • the model is based on the mixed culture of lymphocytes derived from the suspensions of spleen cells from a female C57BI6 mouse and a female BALB/c mouse irradiated at 30 Gy. The spleen cells were mechanically separated and the erythrocytes were eliminated by hypotonic lysis of (ACK - NH4CI 0.15M + KHCO3 1 mM + Na 2 EDTA 0.1 mM).
  • the UptiBlue Viable Cell Counting assay was used to measure quantitatively the in vitro cell proliferation.
  • C57BI6 cells responding cells
  • BALB/c cells stimulating cells
  • the mixed cells culture was incubated for 48 hours at different experimental conditions in an incubator at 37°C 5% CO2.
  • HAUCI 2 0.125; 0.25; 0.5; 1 mM
  • the HL60 cell line is a human leukemia cell line.
  • a patient has leukemia, he undergoes chemotherapy to eliminate leukemia cells and then receives a bone marrow transplant from a healthy patient.
  • hematopoietic stem cell transplantation induces chronic Graft-versus Host Disease (GvHD).
  • GvHD Graft-versus Host Disease
  • First-line therapy for chronic GVHD is based on immunosuppressive agents (corticosteroids with or without cyclosporine) achieving satisfactory response in around 30% of patients.
  • a Phase II study is currently conducted by Medsenic to evaluate if the addition of arsenic trioxide to standard therapy is effective in controlling chronic GvHD and to reduce the duration of corticosteroid therapy.
  • arsenic trioxide is administrated to patients at 0.15mg/kg/day.
  • One aspect of this study is to see if arsenic trioxide is able to act on possibly surviving leukemic cells resistant to chemotherapy, in addition to its effect on the autoimmune features of chronic GvHD, through a process involving the induction of cellular stress on the cells.
  • the HL60 cells (5x10 5 cells/well/strain) were seeded in 96-well plates (Falcon, Corning, reference: 353077) and incubated for 48 hours in complete medium with or without arsenic trioxide at several concentrations: 0.1 ; 0.5; 1 ; 5 and 10mM (AS2O3) in an incubator at 37°C 5% CO2.
  • Figure 1 shows the effect of AS2O3 at increasing concentrations on the production of H2O2, GSH and cell viability (4 independent tests).
  • HL-60 cell viability decreases significantly in the presence of AS2O3 at 1 , 5 and 10 pM (p ⁇ 0.05, p ⁇ 0.001 and P ⁇ 0.001 respectively; Figures 1 B and 1 D).
  • Cell death at 5 and 10mM explains the decrease of H2O2 and GSH production at these AS2O3 concentrations.
  • the dose of 1 mM of AS2O3 was selected to test the effect of combinations of AS2O3 and metal ions on H2O2 production and cell survival of H L60 cells.
  • the biological effect of H2O2 production is still compensated by the production of GSH and the cell viability is preserved.
  • the AS2O3 effect can be modulated by a metal ion.
  • Example 2 Effects of combinations of and metal ions on H 2 O 2 production and cell survival of HL60 cells
  • the HL60 cells (5x10 5 cells/well/strain) were seeded in 96-well plates (Falcon, Corning, reference: 353077) and incubated for 48 hours in complete medium with or without arsenic trioxide 1 mM (AS2O3) with or without different cations or with culture medium alone in an incubator at 37°C 5% CO2.
  • AS2O3 arsenic trioxide 1 mM
  • test 1 or with AS2O3 (1 mM) at 4 pM (test 1 , p ⁇ 0,001 ) and at 2 and 4 pM (test 2, p ⁇ 0,01 and 0.001 , respectively ( Figure 2, upper panels).
  • FeS0 4 alone and with AS2O3 (1 mM) has no significant effect on HL60 viability ( Figure 2, lower panels).
  • HAuCh alone has no significant effect on H2O2 production; this effect is limited at 1 mM with AS2O3 (p ⁇ 0.01 , test 1 ) and at 0.5 mM with AS2O3 (p ⁇ 0.01 , test 2; Figure 3, upper panels).
  • FIAuC alone and with AS2O3 (1 mM) has no significant effect on HL60 viability ( Figure 3, lower panels).
  • MnS0 4 has a significant dose-dependent effect on FI2O2 production at
  • MnSC 0.25, 0.5 and 1 pM (tests 1 and 2, Figure 6, upper panels) and additional effect with AS2O3 at 0.5 and 1 pM (p ⁇ 0.001 ; tests 1 & 2; Figure 6, upper panels) and even with AS2O, at 0.25 (p ⁇ 0.001 ; test 2; Figure 6, left-hand upper panel).
  • MnSC with or without AS2O3, have no real effect on cell viability ( Figure 6, lower panels).
  • MnC with or without AS2O3 has a dose-dependent effect on H2O2 production, but the increases are only significant at 1 pM (p ⁇ 0.001 , test 1 , Figure 7, upper panel). MnSC , with or without AS2O3, has no real effect on cell viability (Figure 7, lower panel).
  • Table 1 summarizes the results obtained on H2O2 production by FIL60.
  • Copper ions have no effect on H L60 viability, alone or in the presence of AS2O3 but significantly increase the effect of AS2O3 on H2O2 production, in a dose- dependent manner.
  • CuCh was chosen for further analysis because it has (and is immediately available in industrial quantities with) a GMP quality grade.
  • Example 3 Effects of combination of AsaOa and CuCI 2 on H2O2 and GSH production and cell survival of HL60 cells.
  • the HL60 cells (5x10 5 cells/well/strain) were seeded in 96-well plates and incubated for 48 hours in complete medium with or without arsenic trioxide at several concentrations (0.1 ; 0.5; 1 ; 5 and 10mM) and with and without CuCh at 1 and 4 mM in an incubator at 37°C 5% CO2. Effects of the combination ofAssO and CuCh :
  • CuCh tested at 1 and 4 pM with a large range of AS2O3 concentrations, shows no additional nor protective effect on HL60 survival but has an additional effect on H 2 O 2 production and a negative effect on GSFI production.
  • Example 4 Effects of combination of and CuCh on GSH production and cell survival of HL60 cells.
  • the HL60 cells (5x10 5 cells/well/strain) were seeded in 96-well plates and incubated for 48 hours in complete medium with or without arsenic trioxide at 1 pM and with and without CuCh at 0.5, 1 , 2 and 4 pM in an incubator at 37°C 5% CO2.
  • Tab e 2 displays the significant results on GSH production.
  • Example 5 Effects of combinations of As 2 Oa and metal ions on the proliferation of C57BL6 mice splenic cells in a mixed lymphocyte reaction
  • MLR Mixed lymphocyte reaction
  • MLR is used as a model of autoimmune reaction which corresponds to an in vitro proliferation of splenic cells from C57BL6 mice exposed to and stimulated by irradiated splenic cells from BalbC mice.
  • This in vitro technique mimics the lymphocyte reaction that happens in vivo in graft versus host disease (GvHD) following allogenic hemapoietic stem cells transplant.
  • In vitro cell proliferation assays were performed on spleen cells from
  • mice co-cultured with previously in vitro irradiated (30 Gray) BALB/c spleen cells.
  • the cells (6x10 5 cells/well/strain) were inoculated in 96-well plates (Falcon, Corning, reference: 353077) and incubated for 48 hours in complete medium with or without arsenic trioxide 1 mM (AS2O3), with or without different cations or with culture medium alone in an incubator at 37°C 5% CO2.
  • AS2O3 arsenic trioxide 1 mM
  • the results presented come from 2 independent experiments, and the cations have different quality levels, as described above in the section regarding materials and methods.
  • Figure 12 shows the controls of proliferation measurement (4 independent tests): splenic cells from C57BL6 mice alone and splenic cells from BALB/c mice alone do not proliferate. In contrast, mixed cells show a lymphocyte reaction and a proliferation equal to that obtained in the presence of mitogen (CD3 5pg/ml/CD28 2pg/ml). Arsenic trioxide (1 mM) completely inhibits cell proliferation in the presence of mitogen.
  • FeSC does not have a significant effect on cell proliferation, either alone or with AS2O3 ( Figure 13).
  • FIAuCh decreases the cell proliferation alone but this effect is limited at 1 mM with AS2O3 and only for test 1 (p ⁇ 0,001 , Figure 14).
  • CuS0 4 and CuC significantly decrease the cell proliferation alone and this effect is significant at 4 pM or 2 and 4 pM with AS2O3 (p ⁇ 0.001 , Figure 17).
  • Table 3 displays the significant results on cell proliferation decrease.
  • Cu2+ is the most efficient metal ion for reducing the mixed lymphocyte reaction; changing the composition of the salt (CuSC or CuCh) or the quality grade does not have any influence on the targeted effect.
  • Example 6 Effects of combinations of As 2 Oa and CuCI 2 on H2O2 and GSH production and cell survival of A20 cells.
  • A20 is a murine lymphoma cell line derived from a spontaneous reticulum cell neoplasm of a Balb/C AnN mouse.
  • arsenic was tested on a murine cell line of cancer cells to study its effect in the same way as for HL60 cells. Indeed, the future in vivo model being performed in mice, it was necessary to check the AS2O3 effect on these murine cells in vitro.
  • the A20 cells (1x10 5 cells/well/strain) were seeded in 96-well plates and incubated for 48 hours in complete medium with or without arsenic trioxide at 1 mM and with and without CuCI2 at 4 concentrations (0.5, 1 , 2 and 4 pM) in an incubator at 37°C 5% CO2.
  • AS2O3 at 1 mM significantly increased the H2O2 production and reduced the A20 viability (p ⁇ 0.001 , test 1 , Figure 18A), but in test 2, AS2O3 only significantly reduced the A20 viability (p ⁇ 0.001 , Figure 18B),
  • CuCh increased the effect induced by AS2O3 on H2O2 production (Tests 1 and 2, Figure 18, left-hand panels). In the presence of AS2O3, CuCh slightly but significantly increased A20 viability at higher concentrations (Test 1 : 2 and 4 mM and Test 2: 4 mM; Figure 18, right-hand panels).
  • Tables 4 and 5 display the significant results on H2O2 and GSH production and A20 viability.
  • HL60 cells 5x10 5 cells/well/strain
  • 96-well plates Falcon, Corning, reference: 353077
  • Ash at several concentrations: 0.1 ;
  • Figures 20 to 23 show the effect of Ash at increasing concentrations on the production of H 2 O 2 and GSH, and cell viability (1 test).
  • Example 8 Effects of combinations of Asia and CuCI 2 on H2O2 production and cell survival of HL60 cells
  • the HL60 cells (5x10 5 cells/well/strain) were seeded in 96-well plates and incubated for 48 hours in complete medium with or without Ash at 1 mM and with and without CuCh at 0.5, 1 , 2 and 4 pM in an incubator at 37°C 5% CO2.
  • Ash at 1 pM has not effect on H 2 O 2 production and cell survival ( Figure 21 ).
  • CuCh significantly increased the effect of Ash (at 1 pM) on H2O2 production ( Figure 21 , left-hand panel). CuCh had no effect on cell survival in presence of Ash ( Figure 21 , right-hand panel).
  • Example 9 Effects of Ash on the proliferative properties of C57BI6 splen cells during a mixed lymphocytic reaction (MLR)
  • the cells (6 c 10 5 cells/well/strain) were seeded in 96-well plates (Falcon, Corning, reference: 353077) and incubated for 48 hours in complete medium supplemented or not, with arsenic trioxide (AS2O3) at 1 pM or with arsenic triiodide (Ash) at 1 pM in presence of mitogen or with copper at increasing concentrations, from 0.5 to 4 pM CuCh.
  • AS2O3 arsenic trioxide
  • Ash arsenic triiodide
  • Cell proliferation was determined by a spectrofluorimeter assay after 24 hours of incubation of the cells with 10% UptiBlue (20 pL in 200 pL of medium).
  • CuCh significantly decreased the proliferation of C57BL6 spleen cells at 1 , 2 and 4 mM (test 1 ) and at 4 pM (test 2).
  • Ash is active, but slightly less than AS2O3 and the synergy with CuCh seems reduced, probably indicating that the important feature is the concentration in the As ion.
  • Example 10 Effects of As 2 Oa and CuCI 2 in a mice model of Graft versus
  • mice (female BALB/c mice-H-2d) previously sub-lethally irradiated with 7.5 Grays from a Gammacel source are grafted with bone marrow (1x10 6 cells) and splenocytes (2x10 6 cells) from mice presenting a low immune compatibility (male B10.D2 mice-H-2b).
  • mice received intraperitoneal injections of arsenic trioxide associated or not with copper chloride (“copper”), 5 times a week for 5 weeks.
  • An irradiation control group was carried out to verify the irradiation efficacy and that the graft had succeeded in the recipient mice.
  • a syngeneic group was grafted with splenocytes and bone marrow from mice of the same genetic background. This control group should not develop chronic GvHD.
  • mice After 5 weeks, the mice should have been euthanized in order to evaluate the effect of the association of copper with arsenic trioxide on the organs affected by chronic GvHD (skin, lung, liver ).
  • Protocol adjustment Following a significant loss of mice in the copper- treated groups, the injections had to be stopped at the end of day 4. The treatment was resumed the following week on day 8 at a different rate until the end of the 5 weeks of treatment. Copper was then injected only twice a week instead of 5 in mice receiving copper, while mice treated with arsenic alone or combined to copper still received 5 injections of ATO per week. Under these new treatment conditions, no more copper-treated mice died.
  • mice The number of mice being greatly reduced, we decided to collect only the blood of the mice in order to perform the transaminase tests, but the organs were not harvested. These experiments show that Copper needs to be reduced to abolish its toxic effect on mice, at least when it is administered via the intraperitoneal route.
  • mice receiving a combined treatment with AS2O3 2.5 pg/g and CuCh (2.5 or 10 pg/g) developed alopecia, which is better than mice receiving only AS2O3 2.5 pg/g (33% alopecia) and even better of mice receiving AS2O3 5 pg/g (20% alopecia) (Figure 24). This confirms that the effects of arsenic are potentiated when co-administered with Copper.
  • mice in the allogeneic group show an increase in ear thickness (vasculitis) compared to mice in the syngeneic group.
  • vasculitis was reduced and in the allogenic group + 5 pg/g, it decreased even more until reaching the same values as the ones of the syngeneic group.
  • Example 11 Effects of As 2 Oa and C11CI2 in a mice model of Graft versus Host Disease (GvHD). with a lower dosage of CuCI 2
  • Table 9 Experimental groups, with the strains of donor and recipient mice and the number of mice per group

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Abstract

La présente invention concerne une combinaison d'un composé d'arsenic et d'un ion métallique, destinée à être utilisée en tant que médicament, l'ion métallique augmentant les effets thérapeutiques de l'arsenic.
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